Constitutive activation of NF-?B, as found in a variety of human cancers including B-cell lymphomas, not only contributes to tumor development and progression but also renders cancer cells resistant to chemotherapeutic agents and radiation therapy. Approaches yielding cancer cell-specific inhibition of NF-?B signaling may hold great promise for targeted and effective cancer therapies. BAFF (B cell activation factor belonging to the TNF family) singling activates NF-?B in B lymphocytes, and emerging evidence indicates that abnormal BAFF signaling contributes to tumorigenesis of B lymphocytes, rendering the BAFF signaling pathway an attractive therapeutic target for B-cell malignancies. How the BAFF signal is transduced to yield activation of NF-?B and how BAFF signaling contributes to B-cell lymphomagenesis have remained largely elusive. We have found that protein kinase PKK (protein kinase C-associated kinase) plays a critical role in NF-?B activation by BAFF in B lymphoma cells. Moreover, we have observed that suppression of PKK expression impairs the survival of human diffuse large B cell lymphoma (DLBCL) cells in vitro, and reduces tumor growth of DLBCL cells implanted into NOD/SCID mice. Thus, we hypothesize that PKK mediates BAFF-induced NF-?B activation and plays a crucial role in the survival/proliferation of human B lymphoma cells. Our preliminary data also indicate that suppression of PKK expression sensitizes DLBCL cells to the treatment with chemotherapeutic agents. Hence, we further hypothesize that therapeutic targeting PKK function may provide efficient therapy for certain B-cell lymphomas. Moreover, the observation that PKK appears dispensable for normal B cell development in mice raises the possibility that PKK may offer a potential window for lymphoma-specific therapeutic intervention. The objectives of the proposed research are to understand the role of PKK in the proliferation/survival of B lymphocytes and the molecular mechanism underlying PKK function. In addition, we will explore the potential of PKK as a therapeutic target for B-cell lymphoma therapy. PUBLIC HEALTH RELEVANCE: B-cell lymphomas are the fifth common cancer type in United States and approximately 20,000 people will die from the disease each year in U.S. The proposed research seeks to identify and characterize the potential therapeutic targets for B-cell lymphoma treatment. Thus, this research may lead to the development of better therapeutic strategies for B-cell lymphoma treatment.